ABSTRACT
To determine local control (LC) and complication rates for patients with intracranial meningiomas who underwent radiosurgery.
One hundred ninety consecutive patients with 206 meningiomas underwent radiosurgery between 1990 and 1998. One hundred forty-seven tumors (77%) involved the cranial base. The median age at the time of radiosurgery was 58 years (range, 20–90 yr). There were 126 female patients (66%). One hundred twelve patients (59%) had undergone one or more previous operations (median, 1; range, 1–5). Twenty-two patients (12%) had either atypical (n = 13) or malignant (n = 9) tumors. The median prescription isodose volume was 8.2 cm3 (range, 0.5–50.5 cm3), and the median tumor margin dose was 16 Gy (range, 12–36 Gy). The median imaging and clinical follow-up periods were 40 and 47 months, respectively.
Overall survival rates for the entire cohort at 5 and 7 years were 82 and 82%, respectively; cause-specific survival rates at 5 and 7 years were 94 and 92%, respectively. The cause-specific survival rates at 5 years for patients with benign, atypical, and malignant tumors were 100, 76, and 0%, respectively (P < 0.0001). The 5-year LC rate was 89%, with 114 tumors (56%) decreasing in size. LC rates were correlated with tumor histological features (P < 0.0001); patients with benign tumors exhibited a 5-year LC rate of 93%, compared with 68 and 0% for patients with atypical or malignant meningiomas, respectively. No correlation was observed between radiation dose and LC rate. Twenty-four patients (13%) experienced treatment-related complications, including cranial nerve deficits (8%), symptomatic parenchymal changes (3%), internal carotid artery stenosis (1%), and symptomatic cyst formation (1%). Only six patients (3%) exhibited decreases in functional status that were directly related to radiosurgery. Tumor volume, tumor margin dose, or previous radiotherapy was not associated with the development of radiation-related complications.
Radiosurgery is an effective management strategy for many patients with meningiomas. Patients with atypical or malignant tumors exhibit high recurrence rates despite the use of radiosurgery, and these patients continue to exhibit worse cause-specific survival rates despite aggressive treatment, including surgery, external-beam radiotherapy, and radiosurgery. Further study is needed to determine the tumor control and complication rates 10 years or more after meningioma radiosurgery.
Meningiomas represent approximately 15% of adult intracranial neoplasms. Surgical resection remains the preferred treatment whenever total removal can be accomplished with acceptable morbidity rates (37). However, even when gross total resection (GTR) has been achieved, the tumor recurrence rate can be substantial when patients are monitored for long periods after surgery. For example, Stafford et al. (39) reported 5- and 10-year progression-free survival rates of 88 and 75%, respectively, on the basis of data for 465 patients with meningiomas who underwent complete resection between 1978 and 1998. However, the intimate relationships between some meningiomas and critical neurovascular structures make complete resection, with acceptable risk, impossible (20, 21, 23). This is significant because of the effects of subtotal resection on this patient population. Kallio et al. (14) reviewed data for 935 patients with meningiomas and observed that the relative risk of death with subtotal resection was 4.2 times greater than that with complete tumor removal.
Numerous studies have documented that postoperative radiotherapy decreases the incidence of tumor recurrence and improves patient survival rates after subtotal meningioma resection (3, 5, 12, 30, 41). Moreover, selected patients were treated with external-beam radiotherapy (EBRT) alone if they were considered medically unfit for surgery or if their tumors were deemed unresectable. Recently, stereotactic radiosurgery has been performed for an increasing number of patients with recurrent or surgically high-risk meningiomas (4, 10, 13, 18, 19, 26, 31, 34–36, 40, 43). In this study, we reviewed our experience with 190 consecutive patients with meningiomas, to determine patient survival rates, local control (LC) rates, and complication rates after stereotactic radiosurgery.
PATIENTS AND METHODS
Patient population
One hundred ninety-three consecutive patients were identified, using a prospectively maintained database, as having undergone meningioma radiosurgery at our center between May 1990 and December 1998. One patient was excluded because of refusal to participate in any research, in accordance with Minnesota statutes; no follow-up data were available for two patients. The clinical, imaging, and treatment parameters and follow-up information for the remaining 190 patients were then analyzed by using the computer database, which was supplemented by medical record review and direct physician and patient contact as needed. Our institutional review board approved all aspects of this study.
One hundred seventy-eight patients had a single tumor, 10 patients had two tumors, 1 patient had three tumors, and 1 patient had five tumors. Therefore, a total of 206 tumors were treated in these 190 patients. Tumor locations are presented in Table 1. Of note, 147 tumors (77%) involved the cranial base. The median age at the time of radiosurgery was 58 years (range, 20–90 yr). There were 126 female patients (66%). One hundred twelve patients (59%) had undergone one or more previous operations (median, 1; range, 1–5). Histological grading was performed by using the World Health Organization criteria for classification of meningiomas. Twenty-two patients (12%) had either atypical (n = 13) or malignant (n = 9) tumors. The median time from diagnosis to radiosurgery was 1.8 years (range, 0.2–31 yr). Sixteen patients (8%) had undergone previous EBRT; an additional 16 patients received radiotherapy in conjunction with radiosurgery for treatment of atypical or malignant tumors. One patient had a radiation-induced tumor secondary to EBRT administered 49 years before radiosurgery, to treat an unrelated benign brain tumor. The median dose of EBRT used for these 32 patients was 50.4 Gy (range, 39.6–63 Gy).
Radiation dosimetry
Radiosurgery was performed with a Leksell gamma knife (Elekta Instruments, Norcross, GA), as previously described (34). A Model U instrument was used before March 1997; thereafter, radiosurgery was performed with a Model B instrument. Typically, multishot dose plans were created to conformally irradiate the often irregularly shaped tumors, to encompass the visible tumor within 2 mm or less. The median number of isocenters used was nine (range, 1–21 isocenters). One hundred ninety-one tumors (93%) were treated at the 50% isodose line. The marginal isodose line used for the prescription dose varied from 33 to 90% for the other 15 tumors. The median prescription isodose volume was 8.2 cm3 (range, 0.5–50.5 cm3). The prescription isodose volume was more than 7.5 cm3 for 110 tumors (53%). Dose prescriptions were based on tumor size, location, and history of previous radiotherapy. Generally, tumor margin doses (TMDs) of 20, 18, and 16 Gy were used for tumor volumes of less than 4.2, 4.2 to 14.1, and more than 14.1 cm3, respectively. The median TMD was 16 Gy (range, 12–36 Gy). The median maximal tumor dose was 32 Gy (range, 20–60 Gy).
Follow-up monitoring and statistical analyses
Patients were instructed to undergo follow-up magnetic resonance imaging (MRI) 6, 12, and 24 months after radiosurgery. If the tumor remained stable at that time, then every-other-year imaging was recommended. One hundred eighty-nine patients (204 tumors) underwent follow-up imaging at a median time of 40 months (range, 2–109 mo) after radiosurgery. One patient with two tumors has refused to undergo follow-up imaging but remains in clinically unchanged condition 9 years after the procedure. The median clinical follow-up period for the 190 patients was 47 months (range, 2–109 mo).
Follow-up MRI scans were compared with scans obtained on the day of radiosurgery. In each case, the tumor diameters in the x, y, and z planes were determined and the MRI scans were reviewed for evidence of any adverse radiation-related effects. Tumor sizes were classified as unchanged, decreased, or increased. Tumor reduction was defined as a decrease in tumor size of more than 2 mm, compared with imaging scans obtained at the time of radiosurgery. Conversely, tumor enlargement of more than 2 mm was considered tumor progression. Tumor growth adjacent to the irradiated tumor was defined as a marginal recurrence. Tumors developing in noncontiguous sites were considered distant recurrences. Patient outcomes were assessed in two ways. First, any new or worsened deficits, as determined on the basis of the patient's last follow-up neurological examination, were described as either minor or major. Minor deficits were defined as those that did not change the functional status of the patient (e.g., partial visual field loss or diplopia), whereas major deficits caused significant declines in performance status (e.g., hemiparesis or lower cranial nerve dysfunction). Second, the performance status of each patient was described as unchanged, improved, or worse, on the basis of the patient's current performance status, compared with that at the time of radiosurgery.
Overall survival (OS), cause-specific survival (CSS), and LC rates were calculated from the date of radiosurgery, using the method described by Kaplan and Meier (15). For CSS rates, only death related to tumor progression or a treatment complication was a censoring event. LC was defined as either unchanged or decreased tumor size. Because of the small numbers of local failures and complications, only univariate analyses were used to assess statistical significance. Comparisons of groups in evaluations of OS, CSS, and LC rates were performed by using the log-rank test. On the basis of a preliminary analysis (data not shown) that demonstrated no difference in any measured end point in comparisons of patients with histologically demonstrated benign tumors and patients who had not undergone previous surgery, the latter group of patients were considered, for statistical purposes, to have benign tumors. Continuous variables were compared by using Student's t test; nonparametric variables were compared by using the χ2 test.
RESULTS
Patient survival rates
Twenty-two of the 190 patients (12%) died during the follow-up period. Seven patients (4%) died as a result of tumor progression; one patient died as a result of hemorrhage into an area of radiation-induced necrosis, 62 months after radiosurgical treatment of a recurrent falcine meningioma. Fourteen patients died as a result of unrelated causes. OS rates at 5 and 7 years for the entire cohort were 82 and 82%, respectively. CSS rates at 5 and 7 years were 94 and 92%, respectively. Patient survival rates grouped according to tumor histological type demonstrated significant differences (P < 0.0001). The 5-year OS rates for patients with benign, atypical, and malignant tumors were 92, 76, and 0%, respectively. The median OS time for patients with malignant meningiomas was only 27 months. The 5-year CSS rates for patients with benign, atypical, and malignant tumors were 100, 83, and 0%, respectively (Fig. 1). Six factors were correlated with improved CSS rates in univariate analyses, i.e., cranial base tumor location (P = 0.0003), smaller tumor volume (P = 0.005), no previous surgery (P = 0.02), female sex (P = 0.002), benign histological features (P < 0.0001), and no previous EBRT (P = 0.004). However, when patients with tumors with atypical or malignant histological features were excluded from analysis, no clinical or treatment-related variables were associated with worse CSS rates for the remaining 168 patients.
Actuarial CSS rates after radiosurgery, stratified on the basis of tumor histological type. F-U, follow-up period.
Actuarial CSS rates after radiosurgery, stratified on the basis of tumor histological type. F-U, follow-up period.
Tumor control rates
On follow-up imaging scans, 72 tumors (35%) were unchanged and 114 (56%) had decreased in size, yielding an overall treated tumor control rate of 91%. Eighteen patients (9%) experienced tumor progression, which was noted a median of 39 months (range, 3–94 mo) after radiosurgery. Tumor progression in these 18 patients was classified as in-field (n = 7), marginal (n = 3), in-field and marginal (n = 1), distant (n = 6), or marginal and distant (n = 1). Overall, the 5-year LC rate was 89%. The 5-year LC rates for benign, atypical, and malignant tumors were 93, 68, and 0%, respectively (P < 0.0001) (Fig. 2). One patient with a benign meningioma that had been previously treated with postoperative EBRT exhibited tumor progression, which was noted 57 months after radiosurgery; the patient underwent repeat resection. Pathological review demonstrated a malignant meningioma. The results of univariate analyses of clinical, treatment, and pathological factors associated with LC are presented in Table 2. When atypical and malignant tumors were excluded from analysis, the only factors that were correlated with decreased LC rates were less than eight isocenters (P = 0.02) and previous or concurrent EBRT (P = 0.001). Importantly, TMD, when tested as either a continuous or noncontinuous (<16 Gy versus ≥16 Gy) variable, was not related to LC rates among patients with benign meningiomas. Because there was an insufficient number of LC events for proper modeling of independent variables, a multivariate analysis was not performed.
Actuarial LC rates after radiosurgery, stratified on the basis of tumor histological type. F-U, follow-up period.
Actuarial LC rates after radiosurgery, stratified on the basis of tumor histological type. F-U, follow-up period.
Univariate Analyses of Factors Related to Local Tumor Control after Meningioma Radiosurgerya
Univariate Analyses of Factors Related to Local Tumor Control after Meningioma Radiosurgerya
Patient outcomes and complications
Clinical outcomes were improved for 15 patients (8%), unchanged for 139 patients (73%), and worse for 28 patients (15%). Eight patients (4%) died as a result of either tumor- or treatment-related causes after radiosurgery. Clinical improvement was related to either resolution of preexisting diplopia or elimination of facial pain. Poor outcomes were primarily attributable to tumor progression. However, six patients (3%) experienced significant neurological impairments that were directly related to radiosurgery and resulted in decreased functional status.
Twenty-four patients (13%) developed treatment-related complications after radiosurgery. Fifteen patients (8%) developed new or worsened cranial neuropathies, which affected multiple nerves in four patients. The cranial nerves affected included the optic (n = 1), oculomotor (n = 2), trigeminal (n = 9), abducens (n = 3), facial (n = 2), and vestibulocochlear (n = 2) nerves. No patient developed a lower cranial nerve deficit after radiosurgery. The median time to the onset of cranial nerve deficits was 6 months (range, 1–98 mo). At the last follow-up examination, the neuropathies of eight patients were unchanged, the neuropathies of two patients were worse, four patients exhibited complete resolution, and one patient was not assessable. Five patients (3%) developed symptomatic T2-weighted signal changes consistent with radiation effects on brain parenchyma. The tumor locations were in the cranial base (n = 2), falx (n = 2), and convexity (n = 1). All five patients had undergone previous surgery; two patients underwent EBRT either before or after radiosurgery. The three patients who did not receive EBRT exhibited later clinical improvements, whereas the two patients who were treated with both radiosurgery and EBRT have exhibited progressive neurological declines. Two patients developed stenosis or occlusion of the internal carotid artery (ICA) after radiosurgical treatment of cavernous sinus meningiomas. One patient exhibited ischemic symptoms, on the side contralateral to the meningioma, 60 months after radiosurgery. A 50% stenosis of the cavernous segment was noted at that time. The other patient experienced cerebral infarction 35 months after radiosurgery, and occlusion of the cavernous ICA was observed. Both patients have exhibited some improvement, although they continue to experience residual neurological deficits resulting from these events. No evidence of tumor progression was noted for either patient; the tumor size and shape remained unchanged from the time of radiosurgery for both patients. The calculated radiation dose to the affected arteries exceeded 25 Gy. Two patients developed cysts adjacent to their treated tumors, 2 years after radiosurgery (Fig. 3). One patient had a recurrent tumor after two previous operations; he received combined radiosurgery (20 Gy at the 50% isodose line, 2.8 cm3) and EBRT (60 Gy). The second patient was treated primarily with radiosurgery (15 Gy at the 50% isodose line, 11.0 cm3). Univariate analyses of clinical and treatment-related factors demonstrated no correlation between patient sex (P = 0.50), tumor histological features (P = 1.00), tumor volume (P = 0.39), TMD (P = 1.00), or EBRT (P = 0.40) and complications arising after radiosurgery.
Post-gadolinium coronal MRI scans obtained for an 82-year-old man with an enlarging right tentorial meningioma. A, MRI scan obtained at the time of radiosurgery. The patient was treated with 15 Gy to the tumor margin (maximum, 30 Gy); the prescription isodose volume was 11.0 cm3. B, MRI scan obtained 2 years after radiosurgery, showing a decrease in tumor size and a small adjacent cyst. C, MRI scan obtained 6 months later, showing cyst enlargement. The patient was treated with a cystoperitoneal shunt.
Post-gadolinium coronal MRI scans obtained for an 82-year-old man with an enlarging right tentorial meningioma. A, MRI scan obtained at the time of radiosurgery. The patient was treated with 15 Gy to the tumor margin (maximum, 30 Gy); the prescription isodose volume was 11.0 cm3. B, MRI scan obtained 2 years after radiosurgery, showing a decrease in tumor size and a small adjacent cyst. C, MRI scan obtained 6 months later, showing cyst enlargement. The patient was treated with a cystoperitoneal shunt.
DISCUSSION
Present series
Our analysis of data for 190 consecutive patients with meningiomas (206 tumors) who underwent radiosurgery between 1990 and 1998 demonstrated 5-year CSS and LC rates of 94 and 89%, respectively. Clearly, the most significant variable correlated with OS, CSS, and LC rates was the tumor histological type. In our series, the 5-year CSS rates for patients with benign, atypical, and malignant tumors were 100, 83, and 0%, respectively. The combined mortality/major morbidity rate was 7%; another 10% of patients experienced either temporary or minor permanent neurological deficits. However, only seven patients (4%) either died (n = 1) or experienced a major permanent neurological deficit that affected their daily functional status (n = 6) as a result of radiosurgery. The remaining patients with poor outcomes all exhibited tumor progression as the primary cause of their decline. Such results are quite favorable, when the characteristics of the patient population are considered. More than three-fourths of our patients had tumors involving the cranial base, and 59% had residual/recurrent tumors after one or more previous operations. Also, 22 patients (12%) had tumors with either atypical or malignant features, and 16 patients (8%) had tumors that had progressed despite previous EBRT. The primary weakness of our study is the relatively short follow-up period for our patients after radiosurgery. Although our median imaging (40 mo) and clinical (47 mo) follow-up periods exceed those in most reports on meningioma radiosurgery published to date, adequate follow-up periods for patients with meningiomas would ideally be 10 years or more. Therefore, this article might be considered to be providing “interim” data on meningioma radiosurgery. Our experience provides further evidence that stereotactic radiosurgery seems to be a safe effective method to provide tumor growth control, with acceptable morbidity rates, for the majority of patients with small or medium-sized meningiomas. Continued diligent follow-up monitoring of a large number of patients is required for complete assessment of the role that radiosurgery should play in the treatment of patients with intracranial meningiomas.
Comparison with published data
Surgical resection of the meningioma, with the involved dura, is considered to be the treatment of choice for meningiomas, whenever this can be accomplished with acceptable morbidity. Kinjo et al. (17) reviewed data for 37 patients with convexity meningiomas who underwent surgery between 1982 and 1992, for whom Grade 0 removal (2-cm dural margin, with excision of all hyperostotic bone) was achieved. No morbidity was observed with this approach, and no patients experienced tumor recurrence during follow-up monitoring that extended beyond 5 years for more than 50% of the patients. However, such aggressive surgery is often not possible because of the tumor location and morphological features, especially for meningiomas of the cranial base. In such cases, complete tumor resection rates of 26 to 86% have been reported (2, 7–9). Complete tumor removal (Simpson Grade I or II) is not a guarantee that the tumor will not recur, however; tumor recurrence rates at 5 years after GTR range from 4 to 18%(3, 5, 29, 30). Moreover, Stafford et al. (39) and Mathiesen et al. (29) noted recurrence rates of 25% when follow-up monitoring extended beyond 10 years. The tumor progression rate after subtotal meningioma resection is of even greater concern. Between 37 and 52% of patients exhibit tumor growth at 5 years (3, 29, 30), and up to 100% of patients exhibit documented tumor progression after 10 years or more (29).
Numerous studies have demonstrated that EBRT decreases tumor recurrence/progression after meningioma surgery and improves patient survival rates (3, 5, 12, 30, 41). Goldsmith et al. (12) reported on 140 patients with meningiomas who received EBRT (54 Gy) after subtotal tumor removal. The progression-free survival rates at 5 and 15 years after EBRT were 89 and 78%, respectively. Moreover, patients treated after 1980, with EBRT based on modern imaging methods, exhibited a 5-year progression-free survival rate of 98%. Similarly, Condra et al. (5) described 262 patients with meningiomas who were treated between 1964 and 1992, with a median follow-up period of 8.2 years. At 15 years, the LC rate was better with subtotal excision combined with EBRT (87%), compared with GTR alone (76%), although the difference was not statistically significant. Those authors also noted that 15-year CSS rates were better with either GTR (88%) or subtotal resection plus EBRT (86%), compared with subtotal resection alone (51%). On the basis of this positive experience, radiosurgery has been increasingly used in the past 15 years as an alternative to EBRT for the treatment of patients with meningiomas who do not exhibit symptoms from mass effect (27).
Several factors make meningioma radiosurgery theoretically appealing. First, these tumors typically can be well observed on MRI scans and are not infiltrative beyond their imaging boundaries. Therefore, complete tumor coverage is possible in the majority of cases, especially when the patient has not undergone previous resection. Second, in radiobiological terms, meningiomas (as benign tumors) represent late-responding targets, which are surrounded by a late-responding tissue (brain) (22). Therefore, there are few benefits of dose fractionation for patients with benign tumors, provided that the radiation is delivered in a conformal manner. Third, although a patient who developed a glioblastoma multiforme 7 years after radiosurgical treatment of a meningioma (with the glioblastoma thus meeting the requirements for a radiation-induced neoplasm) was recently described (46), the incidence of this complication after radiosurgery is likely to be several orders of magnitude less than after EBRT (1). Also, for patients with tumors adjacent to the pituitary gland, the risk of delayed anterior pituitary dysfunction is quite low (6). Last, radiosurgery, performed as an outpatient procedure that is completed in a single day, is more convenient than having to undergo EBRT for a period of 5 to 6 weeks.
The tumor control rates, complications, and outcomes for our patients are quite consistent with observations in recent articles on meningioma radiosurgery. Overall, 81% of our patients exhibited either improved or stable conditions at their last follow-up examinations after radiosurgery. This finding is similar to that of Kondziolka et al. (19), who observed that 91% of patients with meningiomas for whom follow-up data were obtained for 5 to 10 years after radiosurgery remained in neurologically stable condition. The primary difference between these studies is that Kondziolka et al. (19) included only patients with benign meningiomas. Tumor control rates have ranged from 84 to 98% for a number of centers using both gamma knife systems and modified linear accelerators (4, 10, 13, 18, 19, 26, 31, 34–36, 40, 43). However, disease progression outside the prescription isodose volume (marginal or distant recurrence) has been described in most reports and accounts for the majority of radiosurgical failures. For example, Kondziolka et al. (18) observed that 22 of 203 patients (11%) with parasagittal meningiomas exhibited tumor progression after radiosurgery, yielding a calculated 5-year actuarial control rate of 67%. However, when the patients demonstrating tumor growth away from the edge of the radiosurgical volume were excluded, the 5-year LC rate was 85%. Similarly, Hakim et al. (13) noted disease progression for 20 of 127 patients (16%) at a median time of 20 months after radiosurgery; only four failures (3%) were deemed local. In our series, 11 of 18 patients experienced tumor progression outside the irradiated volume. This finding emphasizes the fact that radiosurgery is limited to controlling local disease that can be clearly observed in imaging scans at the time of dose planning. Kondziolka et al. (18) reported an improved 5-year actuarial tumor control rate for patients who had not undergone previous surgery (93 versus 60%); however, the difference did not reached statistical significance (P = 0.08). We also did not observe an association between previous surgery and worse LC rates in our series.
The tumor histological type is probably the most important factor associated with failed meningioma radiosurgery. The 5-year CSS rate for patients with benign meningiomas in our series was 100%, compared with 83% for patients with atypical meningiomas. No patient in our series with a malignant meningioma survived 5 years after radiosurgery. Hakim et al. (13) noted that patients with atypical or malignant meningiomas exhibited 4-year survival probabilities of 83 and 22%, respectively. Ojemann et al. (32) reported outcomes for 22 patients with malignant meningiomas who underwent radiosurgery between 1991 and 1999. Of note, 19 of the 22 patients experienced progression, despite receiving EBRT (median dose, 55 Gy) 4.5 years earlier. The 5-year OS and progression-free survival rates were 40 and 26%, respectively. In a multivariate analysis, patient age and tumor volume were significant predictors of times to progression and survival rates. Of note, five patients (23%) developed radiation-induced necrosis after radiosurgery. Four patients exhibited symptoms, and three required additional surgery to control symptomatic mass effect. Therefore, although our data and those of others do not indicate decreased tumor control rates with TMDs of less than 16 Gy for patients with benign meningiomas, it may be necessary to prescribe higher radiation doses to achieve tumor control for patients with atypical or malignant meningiomas. However, because virtually all patients with atypical or malignant meningiomas have previously undergone EBRT or undergo EBRT concurrently with radiosurgery, the incidence of symptomatic radiation-induced necrosis may limit the overall efficacy of radiosurgery for this unfortunate patient group.
The incidence of radiation-related complications after meningioma radiosurgery is low, and these complications generally affect either cranial nerves or brain parenchyma, depending on the location of the tumor. Studies examining factors associated with cranial neuropathies after radiosurgery have demonstrated that different types of cranial nerves are more susceptible to injury (42), with special sensory nerves (the optic and vestibulocochlear nerves) seeming to be the most radiosensitive. To decrease the risk of visual loss after radiosurgery for patients with tumors adjacent to the optic nerves or chiasm, several articles have recommended administration of no more than 8 Gy to these structures (11, 19, 42). In discussing the 11-year radiosurgical experience at the University of Pittsburgh, Kondziolka et al. (19) noted that only two patients experienced visual complications after radiosurgery. The calculated doses to the optic chiasm for those two patients were 11.5 and 12 Gy. Those authors stated that, because the radiation dose to the optic apparatus has been restricted to less than 8 Gy and more-conformal dose plans have become possible with current software, no patient has experienced visual loss at their center. However, the optic pathways may actually tolerate radiation doses of more than 8 Gy. Leber et al. (24) reviewed data for patients who had undergone radiosurgery in the cavernous sinus and parasellar regions, and those authors observed no cases of optic neuropathy among 31 patients, with doses of up to 10 Gy. Morita et al. (31) reported our early experience with 88 patients with benign meningiomas of the cranial base. In that series, despite a median optic nerve dose of 10 Gy, no patient developed visual loss. Since that report, one patient with a meningioma (of a total of 109 patients at risk) has experienced optic neuropathy, which occurred 86 months after radiosurgery. The dose planning for that patient was based on computed tomographic data, and the estimated radiation dose to the optic nerve was approximately 7 Gy. Of note, that patient had undergone four previous operations and had received EBRT (58.8 Gy) before being referred for radiosurgery. Detailed analysis of optic nerve tolerance, including patients with other benign cranial base tumors, is the subject of ongoing work. However, strict adherence to this 8-Gy guideline may limit the use of radiosurgery for some patients with cranial base meningiomas.
In addition to visual loss, patients with cranial base meningiomas may develop other cranial nerve deficits after radiosurgery. Subach et al. (40) observed that 5 of 62 patients (8%) with meningiomas of the petroclival region developed new permanent cranial injuries. Roche et al. (35) reported on 80 patients who had undergone radiosurgery for treatment of cavernous sinus meningiomas. Only one patient (1.3%) developed diplopia after radiosurgery. However, 21 of 44 patients with eye movement disorders exhibited improvement during a follow-up period of 31 months. In our series, the trigeminal nerve was the most frequently injured. A previous analysis demonstrated that radiation doses to Meckel's cave of more than 19 Gy were correlated with postradiosurgical trigeminal nerve dysfunction (31). Parenchymal radiation injury was noted for five of our patients and was permanent for only two (1%). We did not observe an increased frequency of this complication with falcine tumors, as has been reported elsewhere (18, 38, 43); however, this may be attributable to the small number of treated patients (n = 44) with tumors in this region. It stands to reason that these lesions would be more likely to exhibit edema development, because more brain parenchyma is exposed to radiation, compared with cranial based tumors.
Three complications in our series are worthy of further discussion. Symptomatic ICA injury developed in two patients who underwent radiosurgical treatment of cavernous sinus meningiomas. Both patients experienced permanent neurological deficits as a result of related ischemic events. Roche et al. (35) reported on a patient who developed temporary central facial palsy 14 months after radiosurgical treatment of a cavernous sinus meningioma and was discovered to have occlusion of her intracavernous ICA. The estimated dose to the affected artery was 36 Gy. Because major vascular injuries have been observed after radiosurgical treatment of arteriovenous malformations (44), pituitary adenomas (25), and trigeminal neuralgia (28), every effort should be made, at the time of radiosurgery, to minimize the radiation dose to major arteries. We also observed two patients who developed cysts adjacent to the irradiated tumors, which were symptomatic and required surgical decompression. This complication has been observed after arteriovenous malformation radiosurgery (16, 45) and is thought to be attributable to breakdown of the blood-brain barrier adjacent to the irradiated lesion. Again, limiting the radiation exposure of the adjacent brain parenchyma by using conformal radiation delivery is likely to minimize the risk of this complication. Finally, one patient with a benign meningioma later required repeat surgery, and the tumor exhibited malignant features. Although dedifferentiation of meningiomas has been noted among patients who did not receive radiation (33), this malignant transformation may be secondary to radiosurgery, as previously observed after radiosurgical treatment of vestibular schwannomas (21). In that report, a patient who underwent radiosurgical treatment of a benign recurrent vestibular schwannoma exhibited tumor enlargement 6 years later, and surgical resection was performed. The histological examination revealed a malignant schwannoma, with atypical cells and high mitotic activity. Despite salvage surgery and chemotherapy, the patient developed dissemination of tumor cells within the cerebrospinal fluid and later died. It is too early to accurately determine the incidence of malignant transformation and radiation-induced neoplasm development after meningioma radiosurgery, because of the relatively small number of patients who underwent long-term follow-up monitoring. Therefore, it would be inappropriate for physicians to overemphasize the potential for radiation-induced malignant transformation when discussing this treatment option with patients.
Implications for patient treatment
As mentioned previously, the relative short follow-up periods for these series preclude complete understanding of which patients are best suited for radiosurgery, in comparison with either surgical resection or EBRT. However, enough data have been accumulated in the past decade to allow some general indications for meningioma radiosurgery to be proposed. First, although most tumors exhibit decreases in size if monitored for sufficient periods after radiosurgery, patients with large tumors and symptomatic mass effect should undergo surgical resection as their primary treatment. If complete resection of a large tumor is not possible because of its relationship to critical neurovascular structures, then planned subtotal resection, followed by either EBRT or radiosurgery, should provide long-term tumor control with reduced morbidity rates. Second, all patients with malignant meningiomas, even those with documented evidence of complete resection, should be evaluated for some form of postoperative radiotherapy, to reduce the chance of tumor recurrence. The decision to proceed with EBRT or radiosurgery should be based on the results of postoperative MRI. Patients with no evidence of tumor or diffuse tumor throughout a wide area should receive EBRT. Conversely, patients who are observed to have discrete tumor nodules are better suited for radiosurgery, to minimize the radiation exposure to the surrounding tissues. Because of the high incidence of radiation-related complications among patients who underwent both EBRT and radiosurgery, the combination of radiosurgery and EBRT should be avoided whenever possible. Third, patients who are known to have undergone subtotal resection of a benign tumor, who again have an extended life expectancy, should be strongly considered for postoperative radiotherapy, to reduce the chance of tumor progression (which is almost universal ≥10 years after surgery). Last, patients with small meningiomas of the cranial base are ideal candidates for radiosurgery if the goal of treatment is tumor control with reduced morbidity rates.
CONCLUSIONS
Radiosurgery is an effective management strategy for many patients with meningiomas. Patients with atypical or malignant tumors exhibit high recurrence rates despite the use of radiosurgery, and these patients continue to exhibit worse CSS rates despite aggressive treatment, including surgery, EBRT, and radiosurgery. Additional study of these patients is needed, to determine the tumor control and long-term complication rates 10 years or more after radiosurgery.
REFERENCES
COMMENTS
The authors report their extensive experience with the radiosurgical treatment of meningiomas. This is becoming a common form of therapy for inaccessible meningiomas, particularly if they are small and are located in the cavernous region. Fully one-third of the patients in this series had cavernous meningiomas. The median follow-up period in this study (4 yr) is still short for evaluation of the treatment of meningiomas but is better than some reported in the literature.
It was certainly not surprising that the patients with benign meningiomas fared better than did other patients, but it was surprising how much better the patients with atypical tumors fared, compared with patients with frankly malignant histological types. The majority of the patients with atypical tumors were alive at 5 years, and none of the patients with malignant tumors survived that long. Malignant meningioma rivals malignant glioma for lethality. This fact might support aggressive radiotherapy, but this report suggests that radiosurgery is not the answer.
Philip H. Gutin
New York, New York
The authors of this report have written an excellent review of their experience with gamma knife radiosurgery for the treatment of patients with intracranial meningiomas during an 8-year period. The majority of the tumors were basal in location, and almost 60% of patients had undergone one or more previous operations. Overall, the results for patients with benign meningiomas were excellent, with no tumor-related deaths at 5 years. More than one-half of the tumors had decreased in size by year 5. Patients with benign tumors exhibited a 5-year tumor control rate of 93%. More disappointing results were observed for malignant meningiomas. The incidence of complications was low, and six patients (3%) exhibited decreases in neurological function related to radiosurgery. I think that this work builds on the foundation of previous reports that support the use of stereotactic radiosurgery for patients with difficult-to-treat meningiomas.
Surgical resection may still be the best recommendation for patients for whom complete tumor resection and removal of the neoplastic dural base can be achieved. This is likely possible for most patients with convexity meningiomas, lateral sphenoid meningiomas, falcine tumors, and some anterior basal tumors. The majority of patients with parasagittal or cranial base meningiomas do not undergo resection of the neoplastic dural base, and even nodular disease often remains after surgery. For such patients, the risk of recurrence is high. In past years, surgeons removed as much tumor as possible and often monitored the residual tumor with imaging. Later regrowth was treated with either another operation or radiotherapy. I think that the data obtained in the past 10 years have led to a paradigm shift in meningioma management. Residual tumors in younger patients should be treated with radiosurgery and, for most patients, not monitored. The risk of late recurrence is low, and the safety of this approach is excellent. Large symptomatic meningiomas should be removed, but not at the expense of neurological disability in cases involving high-risk brain locations. The safety of radiosurgery within the cavernous sinus or along the cranial base has allowed radiosurgery to become an excellent partner with microsurgical resection, to improve overall patient outcomes.
Several challenges remain. First, radiosurgery alone does not seem to be a successful solution for patients with malignant meningiomas. We use radiosurgery together with resection and fractionated radiotherapy for these tumors, and results remain disappointing. We essentially “throw the book” at these tumors. We have many patients for whom the target responded adequately but imaging studies performed later demonstrated new tumor growth at other sites. For such patients, we have performed several radiosurgical procedures. Chemotherapy and hormonal therapy have not proved to be very valuable in this setting. Unfortunately, the most malignant tumors are those with the fewest hormone receptors.
Stafford et al. noted some rare problems that should be discussed. They described two patients who developed internal carotid artery injuries after treatment of cavernous sinus meningiomas. One of those patients exhibited ischemic symptoms, on the side contralateral to the meningioma, 5 years after radiotherapy, and 50% stenosis was identified. In our series of meningiomas, which includes more than 600 patients, we have not identified this problem in any patient and we have not observed delayed ischemic deficits. Radiobiological studies have demonstrated that much higher radiation doses are required to close off larger intracranial arteries. I wonder whether these patients had carotid stenosis resulting from tumor invasion rather than irradiation. The authors also identified cyst formation after radiosurgery, which could result from a pronounced regional parenchymal reaction. The authors noted that radiation doses of more than 19 Gy delivered to the area of Meckel's cave were correlated with postradiosurgical trigeminal nerve dysfunction. The incidence of trigeminal nerve-related symptoms has been so low in our experience that it is almost impossible to correlate these symptoms with radiation dose or treatment parameters. Finally, the authors advocate caution in combining radiosurgery with external-beam radiotherapy and state that this combination should be “avoided whenever possible.” This statement requires some discussion. If a patient has previously undergone remote radiotherapy and has a recurrent tumor, management options include resection (likely repeat resection) and radiosurgery. We do not think that radiosurgery should be avoided simply because radiotherapy has previously been administered. However, dose reductions are perhaps necessary, and discussions with the patient and family should include the fact that the chance for radiation-induced side effects might be higher in this setting. We do not think that radiosurgery is contraindicated simply because patients have previously undergone radiotherapy.
In summary, this report adds to the literature on meningioma radiosurgery since our first report 10 years ago (2). As we continue to evaluate long-term effects (1), the role of radiosurgery will be more completely defined. However, we can state with confidence that radiosurgery is an excellent treatment method for patients with intracranial meningiomas and provides good disease control with low risk. There is no doubt that the availability of radiosurgery has affected our use of surgical resection for these tumors.
Douglas Kondziolka
Pittsburgh, Pennsylvania
This is a review of data for 190 consecutive patients with 206 meningiomas who were treated with radiosurgery between 1990 and 1998. Patients with benign histological types and patients with atypical or malignant meningiomas were included. The authors' results confirm those of other authors, indicating that radiosurgery is associated with excellent local control rates for benign meningiomas but relatively poor control rates for atypical or malignant histological types. The complications were focal in nature, and the overall complication rate of 13% is consistent with findings in other reports. The complications were almost exclusively related to cranial nerve damage. When quality-of-life issues were evaluated, 3% of patients demonstrated some decrease in performance related to their radiosurgical treatment and/or meningioma.
I think that this is an honest and complete report, involving a large number of patients. I slightly disagree with the statement that there is no role for radiosurgery for patients with atypical or malignant tumors. Clearly, radiosurgery alone would not be appropriate therapy for such patients. Perhaps a prospective trial integrating radiosurgery with aggressive surgery and fractionated radiotherapy could yield more promising results.
Jay S. Loeffler Radiation Oncologist
Boston, Massachusetts
This article confirms data published elsewhere regarding the effective control of meningiomas after stereotactic radiosurgery. The fairly complete documentation of complications after radiosurgery and the moderately large number of malignant meningiomas treated in this study are noteworthy. Additionally, information regarding the response rates and histological features of these tumors yields important insights into the postradiosurgical biological features of malignant tumors.
The study is hampered, however, by the very heterogeneous nature of the sample with respect to location and histological type, which makes subgroup analyses impractical. Therefore, few conclusions regarding outcomes can be drawn from data on the treatment of meningiomas presenting in specific locations.
I largely agree with the conclusions of this article. Radiosurgery is a safe and effective means of tumor control for meningiomas. It should be considered the treatment of choice for selected meningiomas for which aggressive open surgical resection would be associated with high risks of neurological deficits.
Joseph C.T. Chen
San Diego, California
